Prolongation of morphine analgesia by competitive NMDA receptor antagonist D-CPPene (SDZ EAA 494) in rats

A possible future clinical application of NMDA receptor antagonists is the control of the development of opiate analgesic tolerance. Therefore, the ability of NMDA receptor antagonists to modify the acute analgesic effects of opiates becomes increasingly important. The present study sought to evaluate the analgesic potency of combined administration of morphine (5-20 mg/kg) and a competitive NMDA receptor antagonist D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; 0.3-5.6 mg/kg) in the tail-flick and tail-pinch tests with rats. It was found that D-CPPene significantly increased the duration of morphine analgesia, but there was hardly any evidence for potentiation of morphine analgesia shortly after morphine administration. This effect could only in part be attributed to the D-CPPene-induced disruption of the development of 'learned hyperresponsiveness' (i.e., acquisition of decreased latencies to escape from repeated exposures to noxious stimulation). In addition, the plasma concentration of morphine was not affected by concurrent treatment with D-CPPene.